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Session 2

Pharmacokinetics
and bioavailability
study
Rustamaji
Department of Clinical Pharmacology
Faculty of Medicine
Gadjah Mada University
2008

How drugs act in the body?


Drug

Absorption
Distribution
Metabolism
Excretion

Pharmaco
kinetics

Drug concentration in systemic


circulation
Drug concentration at site of
action
Adverse effect

Pharmaco
dynamics
Therapeutic effect

Drug fate in the body


Other body fluids and tissues

Site(s) of action

Free Drug

Absorption

DrugProtein

Excretion
tes
i
l
o
ab
Met

Free Drug

Metabolism

Pharmacokinetics
A study of the quantification of drugs in the
body

A study of absorption, distribution,


metabolism, and excretion processes of
drugs in the body, based on their blood
concentrations

Pharmacokinetics:

drug concentrations in plasma over time


Plasma drug concentration
Cmax

Minimum Toxic
Concentration

Kel and T1/2


AUC

Tlag

Tmax

Minimum Effective
Concentration

Sub-therapeutic
concentrations

Time

Preclinical pharmacokinetics

Estimate the rate & extent of absorption


Metabolism pattern
Rate and route of elimination
Localization in tissues, protein binding
Multiple dosing
Disclose metabolic product(s)

Etc.

Clinical pharmacokinetics

Metabolic pathways and metabolite profiles


Pharmacokinetic profiles
Pharmacokinetic parameters dosage regimen
Single dosing vs multiple dosing accummulation?
Pharmacokinetic profiles in various conditions:

Age, sex
Meals
Liver/kidney dysfunction
Obesity
Etc.

Most appropriate route of administration


Formulation development, e.g., controlled release, etc.
Quality assurance of products

Widely known as
bioavailability

Pharmacokinetic study

12-24 healthy adult volunteers, 18-40 years,


80-120% ideal body weight to height, overnight fast
Supported by:

clinical examinations and anamnesis

laboratory findings

history of serious disease and allergy to medications

Drug abuse and HIV examinations (!)


Written informed consent
Protocol should be approved by Ethics Committee

Study drugs & blood sampling

Same or equivalent dose(s)


Single or multiple dosing
Condition of drug administration:
fasting
taken with plain water
Light meal? How light?
Light activities during the study
Blood sampling:
at least 3x T1/2 after Tmax
at convenient intervals, minimum 3 time points at each phase
Avoid meals during absorption phase, water ad libitum
Food intake during the study?

Drug assay and data analysis


Standard procedure for drug assay

extraction from the body fluid?


specificity and sensitivity?
reproducibility?

Pharmacokinetic analysis:
single or multi-compartments?
manual or computerized?

Statistical analysis:
Anava + paired T-test
Confidence interval analysis

Bioequivalence studies

Copy products should contain the same amount of the same


therapeutically active ingredients in the same dosage form and
should meet the pharmacopeial standard. However, they are
usually not identical, and in some instances their clinical
interchangeability may be in question

Different excipients, different in stability and bioavailability could


have clinical implications

Regulatory authority need to consider not only the quality,


efficacy, and safety of such pharmaceutical products, but also
their interchangeability
WHO, 1996

Types of BE studies

Comparative bioavailability (BA) studies


Comparative bioefficacy studies:

Pharmacodynamic studies
Clinical trials

Considerations:
When the drugs produce meaningful concentration in
plasma, bioavailability study is preferred
When drug concentration is not measurable, bioefficacy
study is preferred

Design bioavailability study

Cross-over, double-blind if applicable


12-14 adult healthy volunteers
Serial blood collection after administration of study drugs

Justification for
bioequivalence

Rate of bioavailability (Tlag & Tmax)


Extent of bioavailability (Cmax & AUC0-)
Evidence of adverse events

Multiple dosing?
60
50
40
30
20

10
0

10

12

60
50
40
30
20
10
0

10

12

Drugs with narrow therapeutic range


Controlled- release formulation
Drugs use in the national programmes

Justification for
bioequivalence
multiple dosing
First dose:
Rate of bioavailability (T
lag & Tmax)
Extent of bioavailability (C
max & AUC0-)
Evidence of adverse events
At steady state 5th-6th dose):
Rate of bioavailability (T
max)
Extent of bioavailability (C
min, Cmax & AUC0-t)
Fluctuation
Evidence of adverse events
Drug concentration vs time curves
Cmax and Cmin within therapeutic window

Clinical trial for bioefficacy


studies
Standard methodology:

Randomized controlled trial parallel design


Comparison to the innovator
Sample size (minimum 75 volunteers per
group)

A
R

Study drugs & blood sampling

Same or equivalent dose(s)


Single or multiple dosing
Condition of drug administration:
fasting
taken with plain water
Light meal? How light?
Light activities during the study
Blood sampling:
at least 3x T1/2 after Tmax
at convenient intervals, minimum 3 time points at each phase
Avoid meals during absorption phase, water ad libitum
Food intake during the study?

Drug assay and data analysis


Standard procedure for drug assay
extraction from the body fluid?
specificity and sensitivity?
reproducibility?

Pharmacokinetic analysis:
single or multi-compartments?
manual or computerized?

Statistical analysis:
Anova + paired T-test
Confidence interval analysis
80-125%

How to calculate AUC0- and


kel?

AUC0- = AUC0-t + AUCt-

AUC0-t is calculated by applying a trapezoidal rule


AUCt- = Ct/kel

kel (elimination rate constant) is calculated


applying a linear regression analysis to the drug
concentration vs time curve at the elimination
phase

Comparator

Comparator should be a innovator drug


If innovator does not available, comparator
can choose from market leader.
if comparator does not innovator drug, it can
cause bio creep phenomenon

Bio-Creep
Interchangeable
Not Interchangeable

Developing
a slow-release diclofenac formulation
Plasma concentration
(ng/mL)

MEC = 20 ng/mL

Hour
Suryawati, 1989

Theophylline 1x daily
Plasma concentration (ug/mL)
15

1
0

24

48

72

96

120

144

Hours

Suryawati, 1999

Approval of copy/generic
products
Plasma nifedipine concentration (ng/ml)

Time (hours)

Suryawati & Santoso, 1995

Rifampicin
in combination with other anti-TBs, multiple dosing

Plasma RMP concentration on day 15 (ug/ml)

Time (hours)
Suryawati, 1994

Rifampicin capsules, single dose 450


mg
Plasma RMP concentration (mcg/ml)

Time (hours)

Suryawati, 1992

Captopril tablets 25 mg
Plasma concentration (ng/mL)

Suryawati & Santoso, 1994

Time (hours)